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The purpose of this study is to examine effective methods of preventing the transmission of HIV from mother to child during pregnancy, labor and delivery, and breastfeeding. This is one part of the three-part PROMISE study and will be conducted at locations in Africa and other parts of the world where women typically receive a short course of highly active antiretroviral therapy (HAART) during pregnancy and where breastfeeding is common.

Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point

Defined as HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 6-14] visit), confirmed by HIV NAT positivity of a second specimen drawn at a different time point

Postpartum Component: Adherence to the maternal and/or infant ARV regimens, as measured by maternal report and hair measures [ Time Frame: Measured through complete cessation of breastfeeding or 18 months of age, whichever comes first ]

Postpartum Component: Rates and patterns of maternal and infant resistance to the maternal and infant ARV regimens [ Time Frame: Measured at the end of the 5-year study period ]

Postpartum Component: Cost-effectiveness and feasibility of the study ARV prophylaxis regimens [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Death [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: AIDS-defining illness [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Composite endpoint of progression to AIDS-defining illness, death, or a serious non-AIDS cardiovascular, hepatic, or renal event [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: HIV/AIDS-related events [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Cardiovascular or other metabolic events [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Other targeted medical conditions [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or death [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Composite endpoint of HIV/AIDS-related event or World Health Organization (WHO) Clinical Stage 2 or 3 [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Composite endpoint of any condition outlined in Appendix IV of the protocol or death [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Tuberculosis [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Toxicity: Grade 3 or greater laboratory results or signs and symptoms and selected Grade 2 hematologic, renal, and hepatic laboratory results [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Viral resistance [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Self-reported adherence [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Quality of life [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Changes in plasma concentrations of inflammatory and thrombogenic markers [ Time Frame: Measured at the end of the 5-year study period ]

Maternal Health Component: Cost-effectiveness [ Time Frame: Measured at the end of the 5-year study period ]

Postpartum Component: Functional maternal antibody and HIV-envelope binding responses in breast milk and plasma, until cessation of breastfeeding or 18 months postpartum, whichever comes first [ Time Frame: Measured through the time of cessation of breastfeeding or 18 months postpartum, whichever comes first ]

For women, 200 mg orally (one single dose) at onset of labor; for infants, oral suspension (dosing according to birth weight) once a day beginning as soon as possible after birth until there is no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever comes first.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

All infants in the antepartum part of the study will receive NVP each day through 42 days of age or until the Week 6 study visit, whichever is later, regardless of the mother's study arm assignment.

Drug: Nevirapine (NVP)

For women, 200 mg orally (one single dose) at onset of labor; for infants, oral suspension (dosing according to birth weight) once a day beginning as soon as possible after birth until there is no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever comes first.

Women will receive LPV-RTV plus TRV from the Week 1 postpartum visit through the end of maternal follow-up (2 to 5 years). Infants will receive NVP once a day through 6 weeks (42 days) of age.

Drug: Nevirapine (NVP)

For women, 200 mg orally (one single dose) at onset of labor; for infants, oral suspension (dosing according to birth weight) once a day beginning as soon as possible after birth until there is no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever comes first.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

Infants will receive NVP from 6 (up to 14) days of age until there is no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever comes first.

Drug: Nevirapine (NVP)

For women, 200 mg orally (one single dose) at onset of labor; for infants, oral suspension (dosing according to birth weight) once a day beginning as soon as possible after birth until there is no longer any risk of MTCT or until the end of follow-up (104 weeks), whichever comes first.

Antepartum Arm A: 200 mg/300 mg x 2 tablets for a total dose of 400 mg/600 mg orally once ideally at onset of labor or as soon as possible thereafter; 200 mg/300 mg (1 tablet) orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

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Ages Eligible for Study:

Child, Adult, Senior

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Antepartum Component Inclusion Criteria (Step 1):

Confirmed HIV-1 infection, defined as documented positive results from two samples collected at different timepoints prior to study entry. More information on this criterion can be found in the protocol.

Currently pregnant and greater than or equal to 14 weeks gestation based on clinical or other obstetrical measurements

CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

Results of HBV screening (HBsAg testing) available from specimen obtained within 30 days prior to study entry

The following laboratory values from a specimen obtained within 30 days prior to study entry:

Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN)

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Plans to deliver in the study-affiliated clinic or hospital

Has no plans to move outside of the study site area during the 24 months following delivery

Age of legal majority for the respective country and willing and able to provide written informed consent

Intends to breastfeed

Antepartum Component Exclusion Criteria (Step 1):

Participation in PROMISE for a prior pregnancy

Ingestion of any antiretroviral (ARV) regimen with three or more drugs (regardless of duration) or more than 30 days of a single or dual ARV regimen during current pregnancy, according to self report or available medical records

Requires triple ARV therapy (HAART) for own health based on local standard guidelines

World Health Organization (WHO) stage 4 disease

Prior receipt of HAART for maternal treatment indications (e.g., CD4 less than 350 cells/mm^3 or clinical indications); however, could have received ARVs for the sole purpose of prevention of mother-to-child transmission (PMTCT) in previous pregnancies (prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TC-ZDV, and/or sdNVP for PMTCT, as well as use of a short dual nucleoside reverse transcriptase inhibitor [NRTI] "tail" to reduce risk of NVP resistance.)

In labor - at onset or beyond (may be eligible for the Late Presenter registration)

Current or history of tuberculosis (TB) disease (positive PPD without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to study entry (refer to the protocol for a list of prohibited medications)

Fetus detected to have serious congenital malformation (ultrasound not required to rule out this condition)

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

Known to meet the local standard criteria for treatment of HBV (Note: HBV DNA testing or other specialized assessments are not expected to be performed as part of this study. A woman would be excluded only if this information is documented from other sources and she meets the local standard criteria for HBV treatment based on those assessments.)

Social or other circumstances that would hinder long-term follow-up, in the opinion of the site investigator

Currently incarcerated

Antepartum Component Inclusion Criteria (Step 2):

On Antepartum Step 1 Arm A (ZDV + sdNVP + TRV tail); OR on Antepartum Step 1 Arm B or C (maternal triple ARV prophylaxis) and currently receiving triple ARV prophylaxis but does not meet the criteria for switching to a second line regimen and Step 3 entry; OR on Antepartum Step 1 Arm B or C (maternal triple ARV prophylaxis) and is not enrolled in the Postpartum Component or Maternal Health Component but remains in the observational follow-up and is not currently receiving a triple ARV regimen (stopped the regimen)

Reached an indication for triple ARV therapy (HAART) for own health, as specified in the protocol

Willing and able to initiate HAART

Antepartum Component Exclusion Criteria (Step 2):

Antepartum Component Inclusion Criteria (Step 3):

On Antepartum Step 1 Arm B or C or on Step 2

Met the criteria for switching to a second line regimen, as specified in the protocol, while on a triple ARV regimen

Willing and able to initiate an alternative triple ARV regimen

Antepartum Component Exclusion Criteria (Step 3):

Women on Antepartum Step 1 Arm B or C who were not enrolled in the Postpartum Component or Maternal Health Component but remain in observational follow-up and are not currently receiving a triple ARV regimen

Postpartum Component Inclusion Criteria (Step 1):

Participation in the Antepartum Component or registered as a Late Presenter

Intent to breastfeed

Provided written informed consent

Has no plans to move outside of the study site area during the 24 months following delivery

Maternal CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), from a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

The following maternal laboratory values within 30 days prior to entry:

Hemoglobin greater than or equal to 7.0 g/dL

WBC greater than or equal to 1,500 cells/mm^3

ANC greater than or equal to 750 cells/mm^3

Platelets greater than or equal to 50,000 cells/mm^3

ALT less than or equal to 2.5 times the upper limit of normal (ULN)

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Infant alive, healthy, less than or equal to 14 days of age, and uninfected (negative HIV NAT result on specimen drawn prior to study entry)

The following infant lab values on specimen obtained prior to study entry (within 14 days of birth):

Hemoglobin greater than or equal to 10 g/dL

WBC greater than or equal to 1,500 cells/mm^3

ANC greater than or equal to 750 cells/mm^3

Platelets greater than or equal to 50,000 cells/mm^3

ALT less than or equal to 2.5 times the ULN

For Registered Late Presenters: Confirmed maternal HIV-1 infection, defined as documented positive results from two samples collected at different time points at any time prior to entry. More information on this criterion can be found in the protocol.

Postpartum Component Exclusion Criteria (Step 1):

Positive infant HIV NAT result on specimen drawn prior to entry or no infant HIV NAT result on specimen drawn prior to entry

Life-threatening infant illness or birth condition incompatible with life

Infant birth weight less than 2.0 kg

Social or other circumstances that would hinder long-term follow-up, as judged by the site investigator

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

Requires triple ARV therapy (HAART) for own health (includes women who are on Step 2 of the Antepartum Component and women who are on Step 3 of the Antepartum Component for immunologic/clinical disease progression requiring a change in their triple ARV regimen). Note: Women on Step 3 of the Antepartum Component who were never on Step 2 and who entered Step 3 for toxicity or virologic failure without clinical or immunologic disease progression requiring a complete change in the triple ARV regimen are eligible for the Postpartum Component.

Postpartum Component Inclusion Criteria (Step 2):

On Step 1 Arm B (infant prophylaxis); OR on Step 1 Arm A (maternal prophylaxis) and currently receiving triple ARV prophylaxis but does not meet the criteria for switching to a second line regimen and entry into Step 3; OR on Step 1 Arm A (maternal prophylaxis) and not enrolled in the Maternal Health Component but remains in observational follow-up and is not currently receiving a triple ARV regimen (stopped the regimen)

Reached an indication for triple ARV therapy (HAART), as specified in the protocol

Willing and able to initiate HAART

Postpartum Component Exclusion Criteria (Step 2):

Postpartum Component Inclusion Criteria (Step 3):

On Step 1 Arm A or on Step 2

Met the criteria for switching to a second line regimen, as specified in the protocol, while on a triple ARV regimen

Willing and able to initiate an alternate triple ARV regimen

Postpartum Component Exclusion Criteria (Step 3):

On Step 1 Arm A and was not enrolled in the Maternal Health Component but remains in observational follow-up and is not currently receiving a triple ARV regimen

Maternal Health Component Inclusion Criteria (Step 1):

Randomly assigned to triple ARV prophylaxis as part of the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 14 consecutive days of missed dosing) within the previous 30 days; OR randomly assigned to triple ARV prophylaxis in the Antepartum Component but ineligible for the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days

Within 8 weeks after complete breastfeeding cessation is achieved (defined as completely stopping all exposure to breast milk for greater than or equal to 28 days); i.e., within 29 to 84 days of last breast milk exposure, or reached 18 months postpartum (whichever comes first). Women who reach 18 months postpartum while still breastfeeding will be eligible for entry within 2 weeks before and 4 weeks after the Week 74 visit (Week 72-78); OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and her infant is infected and still breastfeeding, she will be eligible for the Maternal Health Component within 42 days of specimen collection for the confirmatory infant HIV NAT; OR if the woman was randomized to triple ARV prophylaxis in the Antepartum Component but mother-infant pair was ineligible for the Postpartum Component she will be eligible for the Maternal Health Component beginning at the Week 1 visit (6-14 days postpartum) through 28 days after delivery; these women should be randomized as soon as possible, ideally within 6-14 days after delivery; OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and breastfeeding risk for MTCT ceases for other reasons (e.g., infant death or permanent removal from home through legal services or adoption) within 28 days of event. More information on this criterion can be found in the protocol.

Provided written informed consent

CD4 cell count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

The following laboratory values on a specimen obtained within 30 days prior to study entry:

ANC greater than or equal to 750 cells/mm^3

Hemoglobin greater than or equal to 7.0 gm/dL

Platelet count greater than or equal to 50,000 cells/mm^3

ALT (SGPT) less than or equal to 2.5 times the ULN

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Intend to remain in current geographical area of residence for the duration of study

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to study entry

Social or other circumstances that would hinder long term follow-up as judged by the site investigator

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

Requires a triple ARV regimen for own health (includes women who are on Step 2 of the Antepartum Component or the Postpartum Component and women who are on Step 3 of the Antepartum Component or the Postpartum Component who entered Step 3 for immunologic/clinical disease progression requiring a change in their triple ARV regimen [HAART]).

Maternal Health Component Inclusion Criteria (Step 2):

On Step 1 Arm B (discontinue the study triple ARV regimen arm); OR on Step 1 Arm A (triple ARV regimen) and currently on the triple ARV regimen but does not meet the criteria for switching to a second line regimen and entry into Step 3

Reached an indication for triple ARV treatment for own health, as specified in the protocol

Willing and able to re-initiate or continue triple ARV therapy

Maternal Health Component Exclusion Criteria (Step 2):

Maternal Health Component Inclusion Criteria (Step 3):

On Step 1 Arm A or Step 2

Meets the criteria for switching to a second line regimen, as specified in the protocol, while on a triple ARV regimen

Willing and able to initiate an alternate triple ARV regimen (HAART)

Maternal Health Component Exclusion Criteria (Step 3):

On Step 1 Arm B

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01061151